The present invention relates to certain polyhydroxylated pentacyclic triterpene acids of formula (I), particularly of formula (I-A), defined hereinafter for use as HMG-CoA reductase inhibitors in the prophylactic and/or therapeutic treatment of a disease, disorder or condition that responds to a reduction of the HMG-CoA reductase activity in a mammal, preferably a human being. The present invention further relates to certain mixtures and plant extracts comprising euscaphic acid and tormentic acid, wherein the amount of euscaphic acid to tormentic acid exceeds a certain ratio. Further, the present invention also relates to a formulation, preferably pharmaceutical or nutraceutical formulation, comprising one or more of said compounds of formula (I), a composition according to the present invention or a plant extract according to the present invention. Also, the present invention relates to a process for obtaining certain polyhydroxylated pentacyclic triterpene acids of formula (I), a composition according to the present invention or a plant extract according to the present invention.
Cholesterol is mainly an issue because blood total cholesterol and low density lipoprotein correlate strongly with coronary heart disease. Cholesterol homeostasis is maintained by a complex mechanism of sterol absorption, anabolism, catabolism and excretion.
Hypocholesteremic agents, i.e. agents that lower the (plasma) cholesterol level by influencing the cholesterol metabolism, are considered to be beneficial for the health of mammals, in particular human beings. For example, by avoiding an increase in arterial cholesterol and preferably by lowering the plasma cholesterol level, the formation of precursors of fatty streak, an early lesion in the atherosclerotic process, may beneficially be influenced. Cholesterol metabolism is complex and hitherto several different approaches using different pathways have been proposed to positively influence the (plasma) cholesterol level in mammals and avoid or reduce hypercholesterolemia, foam cells, fatty streak, atherosclerotic lesion, atheroma and ultimately atherosclerosis.
Generally speaking, cholesterol-lowering functional foods and nutraceuticals may be classified into several different types, mainly based on their respective mechanistic activity. These mechanistic types include intestinal acyl-CoA:cholesterol acyltransferase (ACAT) inhibitors, 3-hydroxy-3-methylglutaryl (HMG-CoA) reductase inhibitors, LDL receptor up-regulators, bile acid reabsorption inhibitors, and cholesterol-7α-hydroxylase (CYP7A1) activators.
For example, grape seed proanthocyanidin extract is reportedly cholesterol-lowering nutraceutical. The hypocholesterolemic activity of grape seed proanthocyanidin is probably mediated by enhancement of bile acid excretion and up-regulation of CYP7A1.
HMG-CoA reductase (3-Hydroxy-3-Methyl-Glutaryl-CoA reductase; enzyme commission designation EC 1.1.1.88) is the rate-controlling enzyme of the mevalonate pathway, the metabolic pathway that produces cholesterol in mammals. Normally, in mammalian cells this enzyme is suppressed by cholesterol derived from the internalization and degradation of low density lipoprotein (LDL, the “bad” cholesterol) via the LDL receptor as well as oxidized species of cholesterol. Competitive inhibitors of the reductase induce the expression of LDL receptors in the liver, which in turn increases the catabolism of plasma LDL and lowers the plasma concentration of cholesterol, an important determinant of atherosclerosis. HMG-CoA reductase is anchored in the membrane of the endoplasmic reticulum.
HMG-CoA reductase is a polytopic, transmembrane protein that catalyzes a key step in the mevalonate pathway, which is inter alia involved in the synthesis of sterols. In mammals, in particular in human beings, the step involving HMG-CoA reductase in the metabolic pathway of the cholesterol synthesis is rate-limiting and therefore represents a major drug target for contemporary cholesterol-lowering drugs. The medical significance of HMG-CoA reductase has continued to expand beyond its direct role in cholesterol synthesis following the discovery that it can offer cardiovascular health benefits independent of cholesterol reduction.
Statins are used to lower serum cholesterol levels as a means of reducing the risk for cardiovascular disease by potently inhibiting the enzyme HMG-CoA reductase, which plays a central role in the production of cholesterol in the liver. Increased cholesterol levels have been associated with cardiovascular diseases, and statins are therefore used in the prevention of these diseases. Statins are very effective for treating cardiovascular disease, with questionable benefit in those without previous cardiovascular disease but with elevated cholesterol levels. Statins are currently the most widely used drugs for prevention and treatment of atherosclerosis. However, statins are reported to have adverse side effects such as hepatotoxicity, muscle pain, kidney damage and weakness.
Statins include for example rosuvastatin, lovastatin, atorvastatin, pravastatin, fluvastatin and simvastatin. Several cholesterol-lowering statins are naturally occurring. Red yeast rice contains statins known as monacolins, including mevastatin and the highly active lovastatin; the latter can also be found in oyster mushrooms.
Acyl-CoA: cholesterol acyltransferase [ACAT; also referred to as sterol O-acyltransferase (SOAT); enzyme commission designation EC 2.3.1.26] catalyzes the acylation of cholesterol to cholesteryl ester with long chain fatty acids and ACAT inhibition is also an useful strategy for treating hypercholesterolemia or atherosclerosis. It has rather recently been revealed that ACAT exists in the form of two isozymes, namely ACAT 1 (expressed in many cells and tissues) and ACAT 2 (expressed specifically in the small intestine and liver), which have different in vivo functions from each other. For example, ursolic acid, oleanolic acid, and betulinic acid, e.g. obtainable from the methanol extracts of the leaves of Lycopus lucidus, are ACAT-inhibitors. Betulinic acid has been described in the literature as potent inhibitor of human ACAT 1 and human ACAT 2.
Other drugs, like ezetimibe, lower the cholesterol level by decreasing cholesterol absorption in the intestine. These may be used alone or together in combination with statins (e.g., ezetimibe and simvastatin).